Derivatives of thiachromane as diuretics



United States Patent US. Cl. 424-275 3 Claims ABSTRACT OF THE DISCLOSUREThis invention relates to diuretic compositions containing derivativesof thiachromanes.

This is a division of application Serial No. 367,202, filed May 13,1964, now U.S. Patent No. 3,355,459.

This invention relates to new derivatives of thiachromanes which can beused as therapeutic substances or for the preparation of suchsubstances, and also to a process for the preparation of these newderivatives.

The new derivatives provided by the invention are compounds of thegeneral formula:

in which A represents a halogen atom or an alkyl radical of lowmolecular weight, and R R and R which may be'the same or different, eachrepresent a hydrogen atom or an alkyl radical of low molecular weight.

Thesenew derivatives of Formula 1 can be prepared by -treating asubstituted thiachromane of the general formula: V

" in which A, R and R have the meanings defined above) with an oxidationagent, in order to obtain a substituted thiachromane 1,1 dioxide,treating this dioxide with "c'hlorosulphonic acid, and thereafterreacting the intermediate formed with a substance of the general formulaNH R (R having the meaning indicated above) and subsequently separatingthederivative of the general Formula 1 obtained; 1

In carrying out the process according to the invention,

:the'stages which have just been mentioned can be represented bythe thefollowing diagrams:

chlorosulv phonation 3,488,424 Ce Patented Jan. 6, 1970 These stages areadvantageously carried out under the following conditions:

The oxidation is effected with the aid of hydrogen peroxide, preferablytitrating about 110 volumes, while heating and in the presence of aceticacid.

The chlorosulphonation with the chlorosulphonic acid is eifected between60 and 150 C., and preferably between 60 and C., while on completion ofthe reaction, the excess of this reactant is eliminated by hydrolysiswith the aid of crushed ice.

When R is not a hydrogen atom, the action of NH R is effected in acommon solvent for the two compounds, which are left in contact witheach other for a few hours before eliminating the solvent; when R is ahydrogen atom, it is expedient to employ liquid ammonia.

The separation is carried out by taking up the residue in water and byprecipitating the desired derivative by slight acidification of themedium.

Thus, it is possible for example to dissolve a. compound of the generalFormula 2, in acetic acid, then to add a large excess of volume hydrogenperoxide, to place the mixture for 30 minutes on a boiling water bathand to pour the solution into cold water. The precipitate which isobtained is centrifuged, washed, dried, then an excess ofchlorosulphonic acid is added and the mixture is placed on a water bathfor about 2 hours. The solution is then poured onto crushed ice and theprecipitate formed is centrifuged, washed with water and dried. Thesulphochloride thus obtained is then added either to an excess of liquidammonia or to an excess of aqueous amine solution NH R After standingfor some time, the excess of reagent is evaporated and the desiredcompound of Formula 1 is precipitated by slightly acidifying the mediumwith hydrochloric acid; it is then centrifuged, washed with water anddried.

The starting materials of the process according to the invention are thesubstituted thiachromanes of general Formula 2.

These compounds can be obtained for example by the processes describedin Berichte (1923)., 56, 1819-1824 or Berichte (1925), 58, 16541676 bycondensing a thiophenol, substituted in the para-position by a halogenatom or an alkyl radical, with a substituted acrylic acid of the generalformula action of N HzRi or its methyl ester, cyclising the derivativewhich is obtained soas to provide a substituted thiachromanone andreducing this latter compound to a thiochnomane of the Formula 2 by theClem-mensen process (Org. Resc. Vol.

1) or by the Wolfi-Kishner process (Org. Resc. Vol 4).

' The investigation of the toxicological and pharmacological propertiesof the new derivatives provided by the invention has shown that thesenew derivatives have a low toxicity (LD perorally, generally greaterthan 2 g./kg. in a mouse) and have interesting diuretic properties.These properties have been proved by giving to .rats orally thederivative under consideration in doses of 5 mg./kg., 10 mg./kg., 50mg./kg. and sometimes 20 0 mg./kg. The results have been set out in thefollowing table, which gives, for each of the derivatives investigated,the diuresis obtained as a function of the administered doses andthecomparison with the diuresis of control animals. i v

TABLE Tested derivatives of Formula (1 Diuretic c y the substituents A,R1, R1 and R3 dmresis TEL/NW6 hours having the following meaning Doselug/kg: Control Treated W' m A R1 R2 R3 per 03 animals animals Controldiur.

Cl H H H 5 0. 36 0. 86 240 0. 36 1. 66 460 50 0. 75 5. 86 780 200 0. 757. 45 990 OH: H H H 5 0. 36 0. 55 150 10 0. 36 1. 53 430 50 0. 40 2. 16540 200 0. 40 3. 91 980 CH3 H CH H 5 0. 51 0. 95 190 10 0. 61 l. 43 28060 0. 85 2. 55 300 CH H H CH3 5 0. 80 1. 160 10 0. 80 2. 45 310 50 0. 852. 95 350 CH CH H H 5 0. 76 0. 76 100 10 0. 76 0. 85 110 50 0. 82 0. 96120 CH3 CH3 CH3 H 5 0. 40 O. 90 10 0. 0. 110 0. 82 0. 72 90 Cl H CH1 H 50. 96 2. 20 230 10 0. 96 4. 36 450 50 0. 38 1. 95 510 OH; H 02H; H 5 0.48 0. 66 140 10 0. 48 0. 91 190 50 O. 38 0. 75 200 One of the newderivatives, namely, 6-methyl-7-sulphamidothiachromane 1,1 dioxide, hasbeen more particularly investigated. This product was administeredperorally to mice in a dose of 2 g./kg., and no death occurred.

In addition, its diuretic activity has been proved in connection with adog. After intravenous injection of 50 mg./ kg. of the derivative andtaking samples of the urine by urethral catheterism, it was possible toconfirm, in connection with the anaesthesised animal, that the diuresiswas six times higher than the normal diuresis one hour after injectionand was still twice as strong three hours afterwards. In connection withthe awakened dog rereceiving perorally 50 mg./kg. of the derivative, itwas found, after taking samples of the urine by a vesicle catheter, thatthe diuresis was tripled during the first three hours following theingestion, and was still doubled with respect to the normal diuresisfive hours afterwards.

In addition, it was established that the products have a low carbonicantianhydrase activity, this permitting a more convenient therapeuticutilisation.

These properties make the products according to the invention substanceswhich are useful in human therapeutics, for example in the treatment ofoedemas, cardiorenal disturbances and obesity.

The present invention also provides pharmaceutical compositions whichcomprise, as active principles, one or more of the derivativescorresponding to the general Formula 1. These compositions are obtainedin such a manner as to be capable of being administered by the digestiveor parenteral tracts; they may be solid or liquid and exist in thepharmaceutical forms at present used in human medicine; the activeprinciple or principles are associated with various excipients normallyemployed in these pharmaceutical compositions, for example talcum, gumarabic, lactose, starch, magnesium stearate, cocoa butter, aqueous ornon-aqueous vehicles, oils, and the various wetting, dispersing andemulsifying agents.

The active therapeutic dose varies according to the subjects, theseriousness of the cases and the effect which is desired. Generallyspeaking, the useful dosology perorally in connection with a human beingis between 0.10 g. and -1 g. per day.

The follow examples illustrate the invention:

EXAMPLE 1 Preparation of2,6-dimethyl-7-sulphamido-thiachromane-1,1-dioxide 34 g. of2,6-dimethylthiachromane were dissolved in 360 cc. of acetic acid and 1cc. of -volume hydrogen peroxide were added. The solution was placed for30 minutes on a boiling water bath and the solution was poured into 1000cc. of cold water. The precipitate formed was centrifuged, washed anddried and there were obtained 30 g. of2,6-dimethylthiachromane-1,1-dioxide. (Yield, 75%; melting point on aKofler bench: 113-114 C.; empirical formula: C H O S; proportion ofsulphur; theoretical, 15.23%; found, 15.36%.)

17 g. of the thus-obtained 2,6-dimethylthiachromane- 1,1-dioxide werethen added to 70 cc. of chloro-sulphonic acid. The mixture was placedfor 2 hours on a water bath at 7090 C. and then this solution was pouredonto crushed ice; a white precipitate was formed, which was washed anddried. There were obtained 20 g. of 2,6- dimethyl-7-chlorosulphonylthiachromane-1,1 dioxide. (Yield, 77% melting point: C.; empiricalformula: C H ClO S proportion of sulphur: theoretical, 20.80%; found,20.89%.)

Finally, 15 g. of this product were added to 100 cc. of liquid ammoniaand left until the ammonia had evaporated. The residue was taken up inwater. The precipitate which formed was acidified, centrifuged andwashed with water. There were obtained 7 g. of2,6-dimethyl-7-sulphamidothiachromane-1,l-dioxide, on crystallisationfrom water. (Melting point: 224-225 C.).

Empirical formula: C H NO S Proportion of sulphur; Theoretical, 2 2.54%;found, 22.46%.

The initial 2,6-dimethylthiachromane could be obtained for example inthe following manner: there was first of all prepared theB-(paratolyl-thio) butyric acid; for this purpose, 44.6 g. ofpara-thiocresol, 36 g. of crotonic acid, 6 drops of a 40% solution oftetrabutyl ammonium hydroxide and 6 drops of piperidine were placed in aspherical flask equipped with a reflux condenser and a thermometer; thismixture was progressively heated on an oil bath until the temperaturereached 230-240" C.

The flask was allowed to cool and the mixture was taken up in water andextracted'by means of benzene. The benzenic layers were washed withwater, the benzene was evaporated and the residuewas distilled with avane pump There were. obtained 54.7 gfof fl-(paratolyl-thio) butyric'acid (B.P. 0.02: 120 124 C.).

50. g. of this acid were then treated with 500 g. of sulphuric acid (66B the mixture was left to stand for several hours and was-then heatedfor 1 hour to 50 to 60 C. The red liquid which was obtained was pouredonto 2 kg. of crushed ice and the thiachromanone formed was extracted bymeans of chloroform. The chloroformic solution was washed and dried andthen distilled. There were obtained 36.7 g. of2,6-dimethyl-4-thiachromanone (M.P.: 6465 C.). v

This product was then reduced, either by a Clemmensen reaction in thepresence of zinc and hydrochloric acid, or by a Wollf-Kishner reactionin the presence of hydrazine. Starting from 36 g. of2,6dimethyl-4-thiachr0rnanone, 17.8 g. (yield: 53.5%) of2,6-dimethylthiachromane,were obtained by Clemmensen reduction and 24.9g. (yield: 75%) of 2,6dimethylthiachromane (melting point: 2832 C.) byWolff-Kishner reduction.

EXAMPLE 2 Preparation of 6-methyl-7-su1phamido-thiachromane- 1,l-dioxide 64.5 g. of 6-methylthiachromane were dissolved in 500 cc. ofacetic acid and 250 cc. of 110-volume hydrogen peroxide were added. Thesolution was placed on a water bath for /2 hour; it was then dilutedwith iced water, the precipitate obtained was recovered, and this waswashed and dried. There were obtained 59.6 g. of 6-methylthiachromane-l,l-dioxide (yield: 77.5%melting point 79-81 C.).

52 g. of this product were added to 250 cc. of chlorosulphonic acid andthe mixture was placed on a water bath at a temperature of 7075 C. for 2hours. It was allowed to cool and poured onto crushed ice; the productwas extracted by means of chloroform, the extracted solutions werewashed and the chloroform was evapo rated. There were obtained 67 g. ofcrude 6-methyl-7- chloro-sulphonyl thiachromane 1,1 dioxide (yield:-86%melting point on a heating stage microscope 158-161-C.).

47 g. of this sulphochloride were introduced into 200 cc. of liquidammonia. The mixture was left to stand at ambient temperature until theammonia evaporated. The residue was taken up in water and the solutionwas acidified. The precipitate formed was centrifuged, washed with waterand dried. There were obtained 30.8 g. of6-methyl-7-sulphamido-thiachromane 1,1 dioxide, recrystallised from2-methoxy ethanol (yield: 49%; melting point on heating stagemicroscope: 236-237" C.).

Empirical formula: C H NO S Proportion of sulphur: Theoretical, 23.27%;found, 22.77%. Proportion of nitrogen: theoretical, 5.08%; found, 5.28%

EXAMPLE 3 Preparation of 3,6-dimethyl-7-sulphamidothiachromane- 1 1-dixide 8.8 g. of 3,6-dimethylthiachromane were dissolved in 50 cc. ofll0-volume hydrogen peroxide to which 100 cc. of acetic acid were added.This was placed on a water bath for 30 minutes. There were obtained 9 g.of 3,6- dimethylthiachromane-1,1-dioxide. (Melting point 102 C. on aheating stage microscope after recrystallisation from ethyl alcohol 95.Proportion of sulfur: theoretical, 15.01%; found, 14.80%.)

6.7 g. of the derivative obtained were added to 50 cc. ofchlorosulphonic acid and the mixture was heated on a water bath for 1%hours to 70 C. After precipitation on crushed ice, extraction withchloroform and evaporation of the solvent, there were obtained 7.4 g. of3,6-

dimethyl 7 chlorosulphonyl-thiachromane-1,1-dioxide which wascrystallised from benzene. (Yield: 75%-- melting point on heating stagemicroscope: 157-158 C.-proportion of chlorine: theoretical, 11.49%;found, 11.53%.)

7 g. of this sulphochloride were introduced into 50 cc. of liquidammonia. After spontaneous evaporation of the ammonia, the substance wastaken up in water, acidified and dried. There were obtained 5 g. of3,6-dimethyl-7- sulphamido-thiachromane-1,l-dioxide, which wascrystallised from water (melting point on heating stage microscope:173-175 C.).

Empirical formula: C H NO S Proportion of sulphur: theoretical, 22.16%;found, 22.10%.

The following derivatives were also prepared in accordance with theprocess described in the above examples:

(a) 6 chloro-7-sulphamido-thiachromane-1,l-dioxide, crystallised from2-methoxy ethanol (melting point: 216-218 C.empirical formula: C I-ll NOS Cl) (b) 2 methyl-6-chloro-7-sulphamido thiachromane 1,1-dioxide,crystallised from 96% ethanol (melting point: 202-204 C.empiricalformula: C H NO S Cl --proportion of sulfur: theoretical, 20.67%; found,20.57 %-proportion of chlorine: theoretical, 11.47%; found, 11.57%).

(c) 2 ethyl-6-methyl-7-snlphamido thiachromane- 1,1-dioxide,crystallised from isopropanol (melting point: 224-225 C.-empiricalformula C H NO S prop0rtion of sulfur: theoretical, 21.14%; found,20.93%).

EXAMPLE 4 Preparation of6-methyl-7-methylsulphamidothiachromane-1,1-dioxide 19.4 g. of6-methyl-7-chlorosulphonyl-thiachromane- 1,1-dioxide, prepared accordingto Example 2, were introduced into 150 cc. of a 33% aqueous solution ofmonomethylamine. They were left in contact for several hours and thesolution was partially evaporated: the precipitate which formed wasacidified and centrifuged, and then it was washed and dried. There wereobtained 13.3 g. of 6 methyl 7 methyl-sulphamido-thiachromane-1,1-dioxide which was crystallised from ethanol. (Yield: 70%melting point onKofler bench: 194-195? C.)

Empirical formula: C H NO S Proportion of sulphur: theoretical, 22.16%;found, 22.50%.

In accordance with this process, there was also prepared 2,6-dimethyl 7methylsulphamido-thiachromane- 1,1-dioxide, which was crystallised from95% ethanol. (Melting point: 204 C.empirical formula:

EXAMPLE 5 Tablets were prepared which conformed to the followingcomposition:

G. 6-methyl-7-sulphamido-thiachromane- 1,1-dioxide 0.200 lactose,talcum, wheat starch, magnesium stearate, icing sugar, quantity to make1 completed tablet 0.500

We claim:

1. A diuretic pharmaceutical composition comprising an effective amountof a compound of the general formula in which A represents a memberselected from the group consisting of halogen atoms and lower alkyl andR R and R each represent a member selected from the group consisting ofhydrogen atoms and lower alkyl and a pharmaceutical excipient.

2. A diuretic pharmaceutical composition comprising an effective amountof 6-methyl-7-sulphamido-thiachromane- 1,1-dioxide and a pharmaceuticalexcipient.

3. A diuretic pharmaceutical composition comprising about 0.2 gram of6-methyl-7-sulphamido-thiachr0mane- 1,1-dioxide and a pharmaceuticalexcipient.

8 References Cited UNITED STATES PATENTS 3,112,307 11/1963 Goldberg etal 260-2-43 3,113,918 5/1964 MacPhillamy et al. 260243 ALBERT T. MEYERS,Primary Examiner I. D. GOLDBERG, Assistant Examiner

